The present invention relates to novel cycloalkyl-benzopyrans and derivatives thereof, compositions containing those compounds, their use as selective estrogen receptor-beta agonists, and their use in the treatment of estrogen receptor-beta mediated diseases such as prostate cancer, benign prostatic hyperplasia, testicular cancer, ovarian cancer, lung cancer, cardiovascular diseases, neurodegenerative disorders, urinary incontinence, central nervous system (CNS) conditions, gastrointestinal (GI) tract conditions, and osteoporosis.
Estrogens play important roles in the development and homeostasis of the reproductive, central nervous, skeletal, and cardiovascular systems of both males and females. The estrogen receptor (ER) is currently the only member of the steroid subfamily of nuclear receptors that has different subtypes. Recently, a new ER isoform, ER-beta (also known as ER-betal) was cloned from a rat prostatic cDNA library and is present in murine and human prostates. Consequently, the previous ER is now designated as ER-alpha. ER-alpha and ER-beta share high amino acid homology, have similar 17-xcex2 Estradiol (E2) binding affinities, and can hetero- or homodimerize to form a signaling complex; Kuiper G G, et al., Endocrinol. 138: 863-70 (1997); Kuiper G G et al., Proc. Natl. Acad. Sci. USA 93: 5925-30 (1996). Although E2 activates both ER-alpha and ER-beta, ER-alpha stimulates transcription and cellular proliferation, while ER-beta suppresses ER-alpha activation. Interestingly, 3-beta, 17-beta-androstanediol and 5-alpha-androstane have been proposed to be endogenous ligands for ER-beta; Weihua Z. et al. PNAS 98:6330-5 (2001). 3-Beta, 17-beta-androstanediol is a major metabolite of dihydrotestosterone (DHT), the 5-alpha-reduced active intracellular androgen in male accessory sex organs. ER-beta activation also stimulates increased glutathione S-transferase and quinone reductase expression. These two enzymes have been shown to possess chemoprotective detoxification properties; Chang W Y et al., Prostate 40: 115-24 (1999); Montano M M et al., J. Biol. Chem. 273: 25443-9 (1998).
With the recent identification of ER-beta, and the recognition that ER-alpha and ER-beta have different biological roles, ER-selective modulators would similarly possess significant clinical utility. Since ER-beta is strongly expressed in a number of tissues including prostate, bladder, ovary, testis, lung, small intestine, vascular endothelium, and various parts of the brain, compounds that selectively modulate ER-beta would be of clinical importance in the treatment of a variety of disease conditions, such as prostate cancer, testicular cancer, ovarian cancer, lung cancer, cardiovascular diseases, neurodegenerative disorders, urinary incontinence, CNS disorders, GI tract conditions, and osteoporosis. Such compounds would have minimal effect on tissues that contain ER-alpha, and thus exhibit different side-effect profiles. Thus, ER-beta agonists will display different therapeutic profiles compared to ER-alpha antagonists or agonists, and would be preferentially beneficial in tissues relying on ER-beta signaling.
The prostate gland produces components that are found in the semen and blood. Some of these are regulatory peptides. The prostate gland comprises stroma and epithelium cells, the latter group consisting of columnar secretory cells and basal non-secretory cells. The proliferation of these basal cells, as well as stroma cells gives rise to benign prostatic hyperplasia (BPH), which is one common prostate disease. BPH is a progressive condition that is characterized by the nodular enlargement of the prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, noncuria, poor urine stream, and hesitation or delay in starting the urine flow. Consequences of BPH can include hypertrophy of bladder smooth muscle, decompensated bladder, and increased incidence of urinary tract infection. The development of BPH is considered to be an inescapable phenomenon for the aging male population. BPH is observed in approximately 70% of males over the age of 70. Drug treatment for BPH currently employs alpha andrenergic antagonists for symptomatic relief or steroid 5-alpha reductase inhibitors to reduce hyperplastic tissue bulk. These approaches are of limited therapeutic benefit.
Mortality due to prostatic cancer when the strategem of watchful waiting is adopted is generally low (9%-15%) in men who have localized tumors. However, these rates pertain to patients with localized disease; they do not necessarily apply to younger men at higher risk. Younger men with stage T1a tumors have a longer projected period of risk than older men with the same stage of the disease and are therefore candidates for a potentially curative treatment. In studies of watchful waiting, the high rates of disease progression (34%-80%) indicate that few clinically evident prostate cancers are dormant.
The present invention relates to novel benzopyran derivatives of formula (I): 
wherein
R1 and R2 are each independently xe2x80x94H, C1-C6 alkyl, xe2x80x94OH, C1-C6 alkoxy, halo, or xe2x80x94CF3;
R3 is xe2x80x94H, C1-C6 alkyl, halo, or xe2x80x94CF3;
Y1, Y2, and Y3 are each independently xe2x80x94H or C1-C6 alkyl; and G is xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94;
with the proviso that when G is xe2x80x94CH2xe2x80x94 and R1, R2, R3, Y2, and Y3 are all xe2x80x94H, then Y1 cannot be methyl;
or a pharmaceutically acceptable salt thereof.
Compounds of the invention are the following:
a) (xc2x1)-2-phenyl-6-hydroxy-cyclopentyl[c]3,4-dihydro-2H-1-benzopyran
b) (xc2x1)-2-(4-fluorophenyl)-6-hydroxy-cyclopentyl[c]3,4-dihydro-2H-1-benzopyran
c) (xc2x1)-2-(4-ethylphenyl)-6-hydroxy-cyclopentyl[c]3,4-dihydro-2H-1-benzopyran
d) (xc2x1)-2-(4-trifluoromethylphenyl)-6-hydroxy-cyclopentyl[c]3,4-dihydro-2H-1-benzopyran
e) (xc2x1)-2-(3-hydroxyphenyl)-6-hydroxy-cyclopentyl[c]3,4-dihydro-2H-1-benzopyran
f) (xc2x1)-2-(4-methylphenyl)-6-hydroxy-cyclopentyl[c]3,4-dihydro-2H-1-benzopyran
In a second embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.
In a further embodiment, the present invention provides medical methods of employing compounds of formula (I) as agonists of estrogen receptor ER beta, further utilized for the treatment of estrogen receptor ER beta-mediated diseases such as prostate cancer, benign prostatic hyperplasia, testicular cancer, cardiovascular diseases, neurodegenerative disorders, urinary incontinence, central nervous system (CNS) conditions, gastrointestinal (GI) tract conditions, and osteoporosis.
As used in this application:
a) the term xe2x80x9chalogenxe2x80x9d refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom;
b) the term xe2x80x9cC1-C6 alkylxe2x80x9d refers to a branched or straight chained alkyl radical containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec butyl, t-butyl, pentyl, hexyl, etc.;
c) the term xe2x80x9cC1-C6 alkoxyxe2x80x9d refers to a straight or branched alkoxy group containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy, hexoxy, etc;
d) the designation xe2x80x9cxe2x80x9d refers to a bond for which the stereochemistry is not designated;
e) the designation xe2x80x9cxe2x80x9d refers to a bond that protrudes forward out of the plane of the page;
f) the designation xe2x80x9cxe2x80x9d refers to a bond that protrudes backward out of the plane of the page;
g) as used in the preparations and examples the following terms have the indicated meanings; xe2x80x9cngxe2x80x9d refers to nanograms; xe2x80x9cxcexcgxe2x80x9d refers to micrograms; xe2x80x9cmgxe2x80x9d refers to milligrams; xe2x80x9cgxe2x80x9d refers to grams; xe2x80x9ckgxe2x80x9d refers to kilograms; xe2x80x9cnmolexe2x80x9d refers to nanomoles; xe2x80x9cmmolxe2x80x9d refers to millimoles; xe2x80x9cmolxe2x80x9d refers to moles; xe2x80x9cxcexcLxe2x80x9d refers to microliters; xe2x80x9cmLxe2x80x9d refers to milliliters; xe2x80x9cLxe2x80x9d refers to liters; xe2x80x9cRfxe2x80x9d refers to retention factor; xe2x80x9cxc2x0 C.xe2x80x9d refers to degrees Celsius; xe2x80x9cbpxe2x80x9d refers to boiling point; xe2x80x9cmm of Hgxe2x80x9d refers to pressure in millimeters of mercury; xe2x80x9cmpxe2x80x9d refers to melting point; xe2x80x9cdecxe2x80x9d refers to decomposition; xe2x80x9c[xcex1]2D0xe2x80x9d refer to specific rotation of the D line of sodium at 20xc2x0 C. obtained in a 1 decimeter cell; xe2x80x9ccxe2x80x9d refers to concentration in g/mL; xe2x80x9cnMxe2x80x9d refers to nanomolar; xe2x80x9cxcexcMxe2x80x9d refers to micromolar; xe2x80x9cmMxe2x80x9d refers to millimolar; xe2x80x9cMxe2x80x9d refers to molar; xe2x80x9cKixe2x80x9d refers to inhibiton constant; xe2x80x9cKdxe2x80x9d refers to dissociation constant; xe2x80x9cpsixe2x80x9d refers to pounds per square inch; xe2x80x9crpmxe2x80x9d refers to revolutions per minute; xe2x80x9cHPLCxe2x80x9d refers to high performance liquid chromatography; xe2x80x9cHRMSxe2x80x9d refers to high resolution mass spectrum; xe2x80x9cTHFxe2x80x9d refers to tetrahydrofuran; xe2x80x9cbrinexe2x80x9d refers to a saturated aqueous solution of sodium chloride; xe2x80x9cL.O.D.xe2x80x9d refers to loss on drying; xe2x80x9cxcexcCixe2x80x9d refers to microcuries; xe2x80x9ci.p.xe2x80x9d refers to intraperitoneally; xe2x80x9ci.v.xe2x80x9d refers to intravenously; and xe2x80x9cDPMxe2x80x9d refers to disintegrations per minute;
h) by the designation 
it is understood that the methyl is attached at the 1-position and the substituent or substituents represented by R can be attached in any of the 2, 3, 4, 5, or 6 positions;
i) the designation 
refers to a phenyl or substituted phenyl and it is understood that either substituent can be attached at any one of positions 1, 2, 3, 4, 5, or 6. It is further understood that when one of the substituents is attached at the 1-position the other substituent represented by R can be attached in any of the 2, 3, 4, 5, or 6 positions, that when one of the substituents is attached at the 2-position the other substituent represented by R can be attached in any of the 1, 3, 4, 5, or 6 positions, that when one of the substituents is attached at the 3-position the other substituent represented by R can be attached in any of the 1, 2, 4, 5, or 6 positions, that when one of the substituents is attached at the 4-position the other substituent represented by R can be attached in any of the 1, 2, 3, 5, or 6 positions, that when one of the substituents is attached at the 5-position the other substituent represented by R can be attached in any of the 1, 2, 3, 4, or 6 positions, and that when one of the substituents is attached at the 6-position the other substituent represented by R can be attached in any of the 1, 2, 3, 4, or 5 positions;
j) the numbering system and naming of the tricyclic ring system of formula (I) is as follows:
where G is xe2x80x94CH2xe2x80x94
where G is xe2x80x94CH2xe2x80x94CH2xe2x80x94
where G is xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94
j) the term xe2x80x9cenantiomeric excessxe2x80x9d or xe2x80x9ceexe2x80x9d refers to the percent by which one enantiomer, E1, is in excess in a mixture of the two enantiomers, E1 plus E2, such that {(E1xe2x88x92E2)÷(E1+E2)}xc3x97100=ee;
The compounds used in the method of the present invention may have one or more asymmetric centers. As a consequence of these chiral centers, the compounds of the present invention occur as racemates and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention. The three main chiral centers, signified as 2, 3, and 4, are illustrated in formula (I).
The preferred relative stereochemistry of compounds of formula (I) is when chiral centers 2, 3, and 4 are all in the cis-configuration, as demonstrated by formulae IB and IC below: 
For the purpose of this invention, a compound designated xe2x80x9cIB racemicxe2x80x9d or xe2x80x9cIC racemicxe2x80x9d, or their structure, indicates a racemic structure of compounds IB and IC. Also, for the purpose of this invention, a compound designated xe2x80x9cID racemicxe2x80x9d or xe2x80x9cIE racemicxe2x80x9d, or their structure as shown below, indicates a racemic structure of compounds ID and IE. 
In order to preferentially prepare one optical isomer over its enantiomer, a number of routes are available. As an example, a mixture of enantiomers may be prepared, and then the two enantiomers may be separated. A commonly employed method for the separation of a racemic mixture is the use of chiral high pressure liquid chromatography. Further details regarding resolution of enantiomeric mixtures may be found in J. Jacques, et al., Enantiomers, Racemates, and Resolutions, (1991). xe2x80x9cThe term xe2x80x9cpharmaceutically acceptable salts thereofxe2x80x9d refers to either an acid addition salt or a basic addition salt.
The expression xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by formula (I). Illustrative inorganic acids that form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic acid, and sulfonic acids such as benzenesulfonic acid, methanesulfonic acid, and 2-hydroxyethanesulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points.
The expression xe2x80x9cpharmaceutically acceptable basic addition saltsxe2x80x9d is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by formula (I). Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline. Either the mono- or di- basic salts can be formed with those compounds.
Preferred embodiments of formula (I) are provided below:
(1) Compounds in which the chiral centers designated as 2, 3, and 4 are all in the cis-position;
(2) Compounds in which G is xe2x80x94CH2xe2x80x94 are preferred;
(3) Compounds in which Y2 and Y3 are both xe2x80x94H are preferred;
(4) Compounds in which R2 is xe2x80x94H or xe2x80x94OH are preferred;
(5) Compounds in which R1 is xe2x80x94H are preferred;
(6) Compounds in which Y1 is xe2x80x94H are preferred;
(7) Compounds in which R3 is xe2x80x94H, methyl, ethyl, fluoro, or xe2x80x94CF3 are preferred.
It is understood that further preferred embodiments of formula (I) can be selected by requiring one or more of the preferred embodiments above. For example, the limitations of (1) can be combined with the limitations of (2); the limitations of (3) can be combined with the limitations of (4); the limitations of (1), (2), (3), (5), (6), and (7) can be combined; and the like.
Illustrative examples of the compounds encompassed by the present invention include the racemic mixtures and specific enantiomers of the following compounds: 
Reaction Schemes
Compounds of formula (I) and intermediates thereof can be prepared as described in Reaction Schemes A through D below. All substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. 
As used herein, R1xe2x80x2, R2xe2x80x2, and Y1xe2x80x2 correspond to the substituents R1, R2, and Y1, respectively, except for when the R1 and R2 substituents would be hydroxy and the Y1 substituent would be xe2x80x94H (making the xe2x80x94Oxe2x80x94Y1 group a hydroxy). In these cases, the corresponding hydroxy group is protected with an alkoxymethylether, such as methoxymethyl (xe2x80x9cMOMxe2x80x9d) or methoxyethoxymethyl (xe2x80x9cMEMxe2x80x9d).
In reaction Scheme A, step 1a, the hydroxy groups on the phenol of formula (2) are protected with a suitable protecting group to provide the protected phenol of formula (4) utilizing techniques and procedures well know to one of ordinary skill in the art. For example, the phenol of formula (2) is combined with a suspension comprising a suitable anhydrous solvent such as anhydrous dimethylform-amide (DMF) and a suitable strong base such as a metal hydride, most preferably sodium hydride. To this suspension is added an amount of alkoxymethyl ether, preferably MOM, which corresponds to a roughly equimolar amount depending on the number of hydroxy groups to be protected on the phenol of formula (2). The reaction may be conducted at room temperature for a time ranging from about 30 minutes to about 2 days. The reaction is then quenched with water and an appropriate ether, such as diethyl ether, and the organic layer is washed with an appropriate base, such as sodium hydroxide, and brine. The protected phenol of formula (4) may be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Scheme A, step 1b, a 2-oxocycloalkanecarboxylate of formula (3) is activated via the triflate to provide the activated cycloalkane carboxylate of formula (5) utilizing procedures and techniques well known in the art; G. T. Crisp et al., J. Org. Chem. 57, 6972-6975 (1992). For example, a methyl-2-oxocycloalkanecarboxylate of formula (3) is dissolved under anhydrous conditions in a suitable solvent, such as tetrahydrofuran, dichloromethane, acetone, ethyl acetate, toluene, or diethyl ether and contacted with a suitable activating agent such as triflic anhydride. The reaction is carried out in the presence of a base, such as N-methylmorpholine, sodium carbonate, triethylamine, N,N-diisopropylethylamine, potassium carbonate or sodium bicarbonate. The reaction is generally carried out at temperatures of from xe2x88x9278xc2x0 C. to ambient temperature. Generally, the reactions require 1 to 24 hours. The reaction may then be quenched. The product of formula (5) can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Scheme A, step 2, the protected phenol of formula (4) is coupled with the activated cycloalkane carboxylate of formula (5) to provide the coupled product of formula (6). For example, the coupling reaction is conducted in the presence of butyllithium, zinc chloride and a Pd species. The reaction is preferably carried out in a suitable solvent such as tetrahydrofuran (THF), and may initially be carried out under anhydrous conditions. Preferably, the protected phenol of formula (4) is dissolved in a suitable solvent such as THF, treated with butyllithium at reduced temperature, zinc chloride in solvent is then added and the temperature allowed to rise to ambient. The palladium species, such as tetrakis(triphenylphosphine)Pd(0), is added together with the activated cycloalkane carboxylate of formula (5) and the temperature is preferably raised to the reflux temperature of the solvent for a period of time ranging from about 6 to 24 hours. The coupled product of formula (6) can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Scheme A, step 3, the coupled product of formula (6) is reduced with a suitable reducing agent to provide the reduced product of formula (7) utilizing techniques and procedures well known in the art. For example, the coupled product of formula (6) is contacted with a suitable reducing agent, such as a palladium species, preferably 5% carbon on palladium, in a suitable solvent or solvent mixture, such as methanol. The reaction is preferably carried out in the presence of a suitable base, such as a trialkylamine, more preferably, triethylamine. The reaction mixture is then heated to a temperature ranging from about 30xc2x0 C. to about reflux for a period of time ranging from about 2 to 24 hours. The reduced product of formula (7) can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Scheme A, step 4, the reduced product of formula (7) can be converted to the Weinreb-amide of formula (8). This reaction can be performed utilizing a reactin of the type described by J. M. Williams, et al., Tetrahedron Letters 36, 5461-5464 (1995). For example, the reduced product of formula (7) is combined with N,O-dimethylhydroxylamine hydrochloride in a suitable aprotic solvent, such as tetrahydrofuran, preferably under anhydrous conditions and cooled to a temperature ranging from about 0xc2x0 C. to about xe2x88x9230xc2x0 C., more preferably about xe2x88x9210xc2x0 C. A suitable Grignard reagent, preferably isopropyl magnesium chloride, is then added in a molar ratio of about 1.5 and reaction mixture is stirred for about 15 minutes to 2 hours. The reaction is then quenched with a proton source such as, for example, saturated ammonium chloride. The Weinreb-amide of formula (8) can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Scheme A, step 5, the Weinreb-amide of formula (8) is combined with the aryl lithium of formula (9) to form the ketone of formula (10). For example, the aryl lithium of formula (9) is added to a solution of Weinreb-amide of formula (8) in a suitable aprotic solvent, such as anhydrous THF, cooled to a temperature ranging from about xe2x88x9220xc2x0 C. to about 5xc2x0 C., preferably 0xc2x0 C., and stirred for a period of time ranging from about 15 minutes to 3 hours. The reaction is then quenched with a proton source, such as, for example, saturated sodium bicarbonate. The ketone of formula (10) can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Scheme A, step 6a or 6b, the ketone of formula (10) is subjected to an acid-catalyzed cyclization followed by reduction of the resulting hemiketal to provide a compound of formula (IA or IAxe2x80x2), which represents the racemic mixture of a compound of formula (I). For example, in step 6a, p-toluenesulfonic acid is added in roughly equimolar proportions to the ketone of formula (10) in a suitable alcohol solvent, such as anhydrous methanol. The mixture is then heated at temperature ranging from 40xc2x0 C. to 60xc2x0 C., preferably 50xc2x0 C., for a period of time ranging from 12 to 24 hours, preferably 18 hours. The reaction is then cooled to ambient temperature and a suitable reducing agent, such as sodium cyanoborohydride, is added along with a suitable indicator such as bromocreosol green in a procedure similar to that described by A. Srikrishna, et. Al., Tetrahedron, vol. 51, no. 11, pp. 3339-3344, 1995. Methanol saturated with hydrochloric acid is then slowly added until a yellow color is maintained. The reaction is stirred for about 1 to 2 hours past the point of final color change. The reaction is then quenched with a suitable proton acceptor, such as saturated sodium bicarbonate. This set of reaction conditions for step 6a will result in a cis-configuration of the chiral centers (e.g., those compounds in IB or IC). The R3SiH/TFA conditions of step 6b will result in a trans-configuration of the chiral centers (e.g., those compounds in ID or IE). The product of formula (IA) or (IAxe2x80x2) can then be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
Alternatively, the coupled product of formula (6) may be synthesized as described in reaction Scheme B. All substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. 
In Scheme B, step 1, the hydroxy groups on the bromophenol of formula (11) are protected with a suitable protecting group to provide the protected bromophenol of formula (12) utilizing techniques and procedures as set forth in Scheme A, step 1a.
In Scheme B, step 2, the protected bromophenol of formula (12) is coupled with the activated cycloalkane carboxylate of formula (5) to provide the coupled product of formula (6) according the techniques and procedures set forth in Scheme A, step 2.
An alternative method for providing specific bromo-substituted intermediates are provided in Scheme C. 
The following examples are presented to further illustrate the preparation of compounds of the present invention. It is not intended that the invention be limited in scope by reason of any of the following examples. 
Stir a suspension of sodium hydride (60% in mineral oil, 3.81 g, 95.45 mmol) in anhydrous DMF (50 mL) under nitrogen atmosphere at 0xc2x0 C. and add a solution of hydroquinone (5.00 g, 45.45 mmol) in anhydrous DMF (50 mL) dropwise. Add to this suspension methoxymethyl chloride (7.2 mL, 95.45 mmol) dropwise with additional gas evolution noted. Allow the reaction to warm to ambient temperature and stir for one hour. Quench the reaction with water and add diethyl ether. Wash the organic layer with 1N sodium hydroxide and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 20% ethyl acetate/hexane to yield the title compound (5.64 g, 63%) as a clear oil. 1H NMR (CDCl3): 6.97 (s, 4H), 5.11 (s, 4H), 3.47 (s, 6H). 
Stir a suspension of sodium hydride (60% in mineral oil, 1.58 g, 39.21 mmol) in anhydrous DMF (50 mL) under nitrogen atmosphere at 0xc2x0 C. and add a solution of 2,6-dibromohydroquinone (5.00 g, 18.67 mmol) in anhydrous DMF (50 mL) dropwise. Add to this suspension methoxymethyl chloride (3.0 mL, 39.21 mmol) dropwise with additional gas evolution noted. Allow the reaction to warm to ambient temperature and stir for one hour. Quench the reaction with water and add diethyl ether. Wash the organic layer with 1N sodium hydroxide and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 20% ethyl acetate/hexane to yield the title compound (3.49 g, 53%) as a clear oil. 1H NMR (CDCl3): 7.23 (s,2H), 5.10 (s, 4H), 3.46 (s, 6H). 
Stir a suspension of sodium hydride (60% in mineral oil, 3.00 g, 74.92 mmol) in anhydrous DMF (50 mL) under nitrogen atmosphere at 0xc2x0 C. and add a solution of methoxyhydroquinone (5.00 g, 35.67 mmol) in anhydrous DMF (50 mL) dropwise. Add to this suspension methoxymethyl chloride (5.2 mL, 74.92 mmol) dropwise with additional gas evolution noted. Allow the reaction to warm to ambient temperature and stir for one hour. Quench the reaction with water and add diethyl ether. Wash the organic layer with 1N sodium hydroxide and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 20% ethyl acetate/hexane to yield the title compound (5.84 g, 72%) as a clear oil. 1H NMR (CDCl3): 7.05 (d, J=8.6, 1H), 6.63 (d, J=2.7, 1H), 6.55 (dd, J=9.0, 2.7, 1H), 5.14 (s, 2H), 5.12 (s, 2H), 3.86 (s, 3H), 3.51 (s, 3H), 3.47 (s, 3H). 
Stir a suspension of sodium hydride (60% in mineral oil, 3.54 g, 88.61 mmol) in anhydrous DMF (100 mL) under nitrogen atmosphere at 0xc2x0 C. and add a solution of 4-methoxyphenol (10.00 g, 80.55 mmol) in anhydrous DMF (50 mL) dropwise. Add to this suspension methoxymethyl chloride (6.7 mL, 88.61 mmol) dropwise. Allow the reaction to warm to ambient temperature and stir for one hour. Quench the reaction with water and add diethyl ether. Wash the organic layer with 1 N sodium hydroxide and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 20% ethyl acetate/hexane to yield the title compound (11.55 g, 85%) as a clear oil. 
Cool a solution of Preparation 2 (1.00 g, 2.81 mmol) to xe2x88x9278xc2x0 C. and add s-BuLi (1.3 M in cylcohexane, 2.10 mL, 2.81 mmol) dropwise. Stir the solution for 15 minutes, then add methyl iodide (0.18 mL, 2.81 mmol) and stir overnight, allowing to warm to ambient temperature. Quench with saturated sodium bicarbonate and add ethyl acetate. Wash with brine, dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 10% ethyl acetate/hexane to yield the title compound (0.66 g, 81%) as a clear oil. 1H NMR (CDCl3): 7.12 (d, J=2.9, 1H), 6.83 (d, J=2.9, 1H), 5.10 (s, 2H), 5.04 (s, 2H), 3.63 (s, 3H), 3.48 (s, 3H), 2.30 (s, 3H). MS calcd 291.1; MS (M+1) 291.2, 293.2. 
This preparation was followed according to J. Org. Chem. 57, 1992, 6972-6975. Stir a solution of methyl 2-oxocylcopentanecarboxylate (10.0 g, 70.42 mmol) in anhydrous dichloromethane (300 mL) cooled to xe2x88x9278xc2x0 C. and add diisopropylethylamine (61.5 mL, 352.1 mmol) and triflic anhydride (14.2 mL, 84.51 mmol). Stir the reaction was stir for 16 hours, allowing it to warm to ambient temperature. Quench the reaction with water and wash with 10% citric acid followed by brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 15% ethyl acetate/hexane to yield the title compound (12.0 g, 63%) as a dark oil which is used without further purification. 1H NMR (CDCl3): 3.79 (s, 3H), 2.75-2.68 (m, 4H), 2.03-15 1.98 (m, 2H). 
Using a method similar to the preparation of Preparation 6, with an exception of using methyl 2-oxo-1-cycloheptanecarboxylate (5.00 g, 29.37 mmol) to yield the title compound (4.34 g, 49%) as a dark oil. 
Stir a solution of methyl 2-oxo-5,5-dimethyl-cyclopentanecarboxylate (J. Chem. Soc., 1996, 1539-1540) (0.85 g, 5.00 mmol) in anhydrous dichloromethane (15 mL) cooled to xe2x88x9278xc2x0 C. and add diisopropylethylamine (4.4 mL, 25.00 mmol) and triflic anhydride (1.0 mL, 6.00 mmol). Stir the reaction was stir for 16 hours, allowing it to warm to ambient temperature. Quench the reaction with water and wash with 10% citric acid followed by brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 15% ethyl acetate/hexane to yield the title compound (1.16 g, 77%) as a dark oil which is used without further purification. 1H NMR (CDCl3): 3.78 (s, 3H), 2.64 (t, J=7.1, 2H), 1.83 (t, J=7.1, 2H), 1.18 (s, 6H). 
Stir a solution of methyl 2-oxo-5,5-diethyl-cyclopentanecarboxylate (J. Chem. Soc., 1996, 1539-1540) (2.94 g, 14.85 mmol) in anhydrous dichloromethane (100 mL) cooled to xe2x88x9278xc2x0 C. and add diisopropylethylamine (13.0 mL, 74.25 mmol) and triflic anhydride (3.0 mL, 17.82 mmol). Stir the reaction was stir for 16 hours, allowing it to warm to ambient temperature. Quench the reaction with water and wash with 10% citric acid followed by brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 15% ethyl acetate/hexane to yield the title compound (3.96 g, 82%) as a dark oil which is used without further purification. 1H NMR (CDCl3): 3.78 (s, 3H), 2.60 (t, J=7.4, 7.8, 2H), 1.83 (t, J=7.8, 7.1, 2H), 1.46 (q, J=7.4, 7.4, 7.4, 4H), 0.91 (t, J=7.4, 7.4, 6H). 
Cool a solution of Preparation 1 (0.95 g, 4.81 mmol) in anhydrous THF (25 mL) to xe2x88x9278xc2x0 C. and add t-BuLi (1.7M in pentane, 2.8 mL, 4.81 mmol). Stir the solution 15 minutes, then warm to 0xc2x0 C. Add a solution of zinc chloride (1.0 M in diethyl ether, 4.8 mL, 4.81 mmol) dropwise and allow the resulting solution to warm to ambient temperature. Cannulate this solution into a solution of Preparation 6 (0.88 g, 3.21 mmol) and tetrakis(triphenylphosphine)Pd(0) (0.37 g, 0.32 mmol) in anhydrous THF (25 mL) and heat the resulting solution to 50xc2x0 C. for 16 hours. Cool the reaction to ambient temperature and quench with water. Add ethyl acetate and wash the resulting organic layer with saturated sodium bicarbonate and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 30% ethyl acetate/hexane to yield the title compound (0.56 g, 55%) as a clear oil. 1H NMR (CDCl3): 7.04 (d, J=9.0, 1H), 6.90 (dd, J=3.1, 9.0, 1H), 6.81 (d, J=3.1, 1H), 5.10 (s, 2H), 5.02 (s, 2H), 3.56 (s, 3H), 3.46 (s, 3H), 3.42 (s, 3H), 2.80 (t, J=8.6, 8.2, 4H), 2.05-1.95 (m, 2H). MS calcd 322.2; MS (M+1) 323.1. 
Cool a solution of Preparation 1 (2.00 g, 10.13 mmol) in anhydrous THF (25 mL) to xe2x88x9278xc2x0 C. and add t-BuLi (1.7M in pentane, 5.9 mL, 10.13 mmol). Stir the solution 15 minutes, then warm to 0xc2x0 C. Add a solution of zinc chloride (1.0 M in diethyl ether, 10.1 mL, 10.13 mmol) dropwise and allow the resulting solution to warm to ambient temperature. Cannulate this solution into a solution Preparation 7 (2.04 g, 6.75 mmol) and tetrakis(triphenylphosphine)Pd(0) (0.40 g, 0.34 mmol) in anhydrous THF (25 mL) and heat the resulting solution to 50xc2x0 C. for 16 hours. Cool the reaction to ambient temperature and quench with water. Add ethyl acetate and wash the resulting organic layer with saturated sodium bicarbonate and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 20% ethyl acetate/hexane to yield the title compound (2.13 g, 90%) as a colorless oil. 1H NMR (CDCl3): 6.98 (d, J=9.0, 1H, 6.85 (dd, J=3.1, 9.0, 1H), 6.65 (d, J=3.1, 1H), 5.10 (s, 4H), 3.45 (s, 3H), 3.44 (s, 3H), 3.38 (s, 3H), 2.56-2.50 (m, 4H), 1.84-1.80 (m, 2H), 1.65-1.60 (m, 4H). MS calcd 350.1; MS (M+1) 351.1. 
Cool a solution of Preparation 3 (2.18 g, 9.56 mmol) in anhydrous THF (40 mL) to xe2x88x9278xc2x0 C. and add t-BuLi (1.7M in pentane, 6.2 mL, 10.52 mmol). Stir the solution 15 minutes, then warm to 0xc2x0 C. Add a solution of zinc chloride (1.0 M in diethyl ether, 9.6 mL, 9.56 mmol) dropwise and allow the resulting solution to warm to ambient temperature. Cannulate this solution into a solution of Preparation 6 (2.62 g, 9.56 mmol) and tetrakis(triphenylphosphine)Pd(0) (0.55 g, 0.48 mmol) in anhydrous THF (40 mL) and heat the resulting solution to 50xc2x0 C. for 16 hours. Cool the reaction to ambient temperature and quench with water. Add ethyl acetate and wash the resulting organic layer with saturated sodium bicarbonate and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 20% ethyl acetate/hexane to yield the title compound (0.62 g, 18%) as a colorless oil. 1H NMR (CDCl3): 6.57 (d, J=2.7, 1H), 6.40 (d, J=2.7, 1H), 5.11 (s, 2H), 4.89 (s, 2H), 3.81 (s, 3H), 3.58 (S, 3H), 3.47, (s, 3H), 3.44 (s, 3H), 2.83-2.77 (m, 4H), 2.03-1.96 (m, 2H). MS calcd 352.1; MS (M+1) 353.1. 
Cool a solution of Preparation 1 (1.13 g, 5.71 mmol) in anhydrous THF (40 mL) to xe2x88x9278xc2x0 C. and add t-BuLi (1.7M in pentane, 3.4 mL, 5.71 mmol). Stir the solution 15 minutes, then warm to 0xc2x0 C. Add a solution of zinc chloride (1.0 M in diethyl ether, 5.7 mL, 5.71 mmol) dropwise and allow the resulting solution to warm to ambient temperature. Cannulate this solution into a solution of Preparation 8 (1.15 g, 3.80 mmol) and tetrakis(triphenylphosphine)Pd(0) (0.55 g, 0.48 mmol) in anhydrous THF (40 mL) and heat the resulting solution to 50xc2x0 C. for 16 hours. Cool the reaction to ambient temperature and quench with water. Add ethyl acetate and wash the resulting organic layer with saturated sodium bicarbonate and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 15% ethyl acetate/hexane to yield the title compound (0.42 g, 32%) as a colorless oil. 1H NMR (CDCl3): 7.05 (d, J=9.0, 1H), 6.92 (dd, J=3.1, 9.0, 1H), 6.62 (d, J=3.1, 1H), 5.11 (S, 2H), 5.01 (s, 2H), 3.49 (s, 3H), 3.46 (s, 3H), 3.40 (s, 3H), 2.70 (t, J=7.0, 7.4, 2H), 1.86 (t, J=7.4, 7.0, 2H), 1.59 (bs, 6H). MS calcd 350.1; MS (M+1) 351.1. 
Cool a solution of Preparation 1 (3.64 g, 18.38 mmol) in anhydrous THF (50 mL) to xe2x88x9278xc2x0 C. and add t-BuLi (1.7M in pentane, 3.4 mL, 5.71 mmol). Stir the solution 15 minutes, then warm to 0xc2x0 C. Add a solution of zinc chloride (1.0 M in diethyl ether, 10.8 mL, 18.38 mmol) dropwise and allow the resulting solution to warm to ambient temperature. Cannulate this solution into a solution of Preparation 9 (3.96 g, 12.25 mmol) and tetrakis(triphenylphosphine)Pd(0) (0.71 g, 0.61 mmol) in anhydrous THF (50 mL) and heat the resulting solution to 50 C for 16 hours. Cool the reaction to ambient temperature and quench with water. Add ethyl acetate and wash the resulting organic layer with saturated sodium bicarbonate and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 15% ethyl acetate/hexane to yield the title compound (3.30 g, 84%) as a colorless oil. 1H NMR (CDCl3): 7.05 (d, J=9.0, 1H), 6.89 (dd, J=3.1, 9.0, 1H), 6.62 (d, J=2.7, 1H), 5.11 (s, 2H), 5.00 (s, 2H), 3.49 (s, 3H), 3.46 (s, 3H), 3.40 (s, 3H), 2.65 (bt, J=7.8, 7.0, 2H), 1.87 (t, J=7.8, 7.4, 2H), 1.45-1.38 (m, 4H), 0.90-0.82 (m, 6H). MS calcd 378.1; MS (M+1) 379.1. 
Cool a solution of Preparation 5 (1.24 g, 4.26 mmol) in anhydrous THF (20 mL) to xe2x88x9278xc2x0 C. and add s-BuLi (1.3M in cyclohexane, 3.3 mL, 4.26 mmol). Stir the solution 15 minutes, then warm to 0xc2x0 C. Add a solution of zinc chloride (1.0 M in diethyl ether, 4.3 mL, 4.26 mmol) dropwise and allow the resulting solution to warm to ambient temperature. Cannulate this solution into a solution of Preparation 6 (1.17 g, 4.26 mmol) and tetrakis(triphenylphosphine)Pd(0) (0.24 g, 0.21 mmol) in THF (20 mL) and heat the resulting solution to 50xc2x0 C. for 16 hours. Cool the reaction to ambient temperature and quench with water. Add ethyl acetate and wash the resulting organic layer with saturated sodium bicarbonate and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 20% ethyl acetate/hexane to yield the title compound (0.54 g, 38%) as a colorless oil. 1H NMR (CDCl3): 6.80 (d, J=2.4, 1H), 6.61 (d, J=2.3, 1H), 5.09 (s, 2H), 4.79 (s, 2H), 3.57 (s, 3H), 3.48 (s, 3H), 3.46 (s, 3H), 2.83-2.76 (m, 4H), 2.29 (s, 3H), 2.02-1.96 (m, 2H). MS calcd 336.2; MS (M+1) 337.2. 
Cool a solution of Preparation 4 (2.00 g, 11.90 mmol) in anhydrous THF (20 mL) to xe2x88x9278xc2x0 C. and add s-BuLi (1.3M in cyclohexane, 7.7 mL, 13.09 mmol). Stir the solution 15 minutes, then warm to 0xc2x0 C. Add a solution of zinc chloride (1.0 M in diethyl ether, 11.9 mL, 11.90 mmol) dropwise and allow the resulting solution to warm to ambient temperature. Cannulate this solution into a solution of Preparation 6 (3.26 g, 11.90 mmol) and tetrakis(triphenylphosphine)Pd(0) (0.69 g, 0.58 mmol) in THF (20 mL) and heat the resulting solution to 50xc2x0 C. for 16 hours. Cool the reaction to ambient temperature and quench with water. Add ethyl acetate and wash the resulting organic layer with saturated sodium bicarbonate and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 20% ethyl acetate/hexane to yield the title compound (1.28 g, 38%) as a colorless oil which is a mixture of regioisomers by 1H NMR. MS calcd 292.1; MS (M+1) 293.1. 
To a suspension of 5% palladium on carbon (0.27 g) in methanol (15 mL) add a solution of Preparation 10 (0.27 g, 0.84 mmol) in methanol (10 mL). Place the mixture on a Parr shaker under hydrogen (60 psi) at 40xc2x0 C. for twelve hours. Purge the reaction with nitrogen and filter with celite. Concentrate the filtrate in vacuo and flash chromatograph with 30% ethyl acetate/hexane to yield the title compound (0.20 g, 75%) as a clear oil. 1H NMR (CDCl3): 6.98 (d, J=8.6, 1H), 6.86 (d, J=3.1, 1H), 6.81 (dd, J=3.1, 9.0, 1H), 5.1 (s, 2H), 5.08 (s, 2H), 3.64-3.59 (m, 1H), 3.50 (s, 3H), 3.45 (s, 3H), 3.39-3.30 (m, 1H), 3.19 (s, 3H), 2.12-1.98 (m, 4H), 1.93-1.82 (m, 1H), 1.72-1.63 (m, 1H), MS calcd 324.2; MS (M+1) 325.2. 
To a suspension of 5% palladium on carbon (0.25 g) in methanol (25 mL) add a solution Preparation 15 (0.54 g, 1.61 mmol) in methanol (10 mL). Place the mixture on a Parr shaker under hydrogen (60 psi) at 40xc2x0 C. for twelve hours. Purge the reaction with nitrogen and filter with celite. Concentrate the filtrate in vacuo and flash chromatograph with 20% ethyl acetate/hexane to yield the title compound (0.49 g, 89%) as a clear oil. 1H NMR (CDCl3): 6.69 (d, J=2.8, 1H), 6.65 (d, J=3.1, 1H), 5.04 (m, 2H), 4.93 (dd, J=5.9, 16.0, 2H), 3.73-3.67 (m, 1H), 3.57 (s, 3H), 3.42 (s, 3H), 3.25-3.19 (m, 4H), 2.25 (s, 3), 2.17-2.12 (m, 1H), 2.05-1.85 (m, 4H), 1.70-1.60 (m, 1H). MS calcd 338.2; MS (M+1) 339.2. 
To a suspension of 5% palladium on carbon (0.38 g) in methanol (35 mL) add a solution of Preparation 11 (0.75 g, 2.14 mmol) in methanol (10 mL). Place the mixture on a Parr shaker under hydrogen (60 psi) at 40xc2x0 C. for twelve hours. Purge the reaction with nitrogen and filter with celite. Concentrate the filtrate in vacuo and flash chromatograph with 20% ethyl acetate/hexane to yield the title compound (0.63 g, 84%) as a clear oil. 1H NMR (CDCl3): 6.95 (d, J=9.0, 1H), 6.85 (d, J=3.1, 1H), 6.79 (dd, J=3.1, 9.0, 1H), 5.15 (s, 2H), 5.13-5.05 (m, 2H), 3.56-3.51 (m, 1H), 3.50 (s, 3H), 3.45 (s, 3H), 3.30 (s, 3H), 3.08-3.04 (m, 1H), 2.23-2.17 (m, 1H), 2.04-1.80 (m, 6H), 1.55-1.40 (m, 3H). MS calcd 352.2; MS (M+1) 353.2. 
To a suspension of 5% palladium on carbon (0.08 g) in methanol (50 mL)/triethylamine (1.0 mL) add a solution of Preparation 12 (0.62 g, 1.76 mmol) in methanol (10 mL). Place the mixture on a Parr shaker under hydrogen (60 psi) at 40xc2x0 C. for twelve hours. Purge the reaction with nitrogen and filter with celite. Concentrate the filtrate in vacuo and flash chromatograph with 20% ethyl acetate/hexane to yield the title compound (0.50 g, 81%) as a clear oil. 1H NMR (CDCl3): 6.50 (d, J=2.7, 1H), 6.44 (d, J=2.7, 1H), 5.14-5.05 (m, 4H), 3.80 (m, 4H), 3.58 (s, 3H), 3.46 (s, 3H), 3.25 (m, 4H), 2.15-2.09 (m, 1H), 2.07-1.90 (m, 4H), 1.72-1.64 (m, 1H). MS calcd 354.1; MS (M+1) 355.1. 
To a suspension of 5% palladium on carbon (0.05 g) in methanol (50 mL)/triethylamine (1.0 mL) add a solution of Preparation 13 (0.42 g, 1.19 mmol) in methanol (10 mL). Place the mixture on a Parr shaker under hydrogen (60 psi) at 40xc2x0 C. for twelve hours. Purge the reaction with nitrogen and filter with celite. Concentrate the filtrate in vacuo and flash chromatograph with 20% ethyl acetate/hexane to yield the title compound (0.16 g, 38%) as a clear oil. 1H NMR (CDCl3): 7.00 (d, J=8.2, 0.5H), 6.94 (d, J=7.8, 0.5H), 6.84-6.75 (m, 1.5H), 6.67 (d, J=3.1, 0.5H), 5.12-5.01 (m, 4H), 3.77 (d, J=9.0, 0.5H), 3.64 (d, J=11.3, 0.5H), 3.52 (s, 1.5H), 3.49 (s, 1.5H), 3.48-3.43 (s, 4.5H), 3.35 (s, 1.5H), 2.55-2.42 (m, 0.5H), 2.17-2.02 (m, 1H), 1.95-1.88 (m, 0.5H), 1.81-1.75 (m, 1H), 1.69-1.60 (m, 0.5H), 1.55-1.50 (m, 0.5H), 1.15 (s, 1.5H), 1.01 (s, 1.5H), 0.78 (s, 3H). MS calcd 352.2; MS (M+1) 353.2. 
To a suspension of 5% palladium on carbon (0.58g) in methanol (50 mL)/triethylamine (1.0 mL) add a solution of Preparation 14 (1.25 g, 3.89 mmol)in methanol (10 mL). Place the mixture on a Parr shaker under hydrogen (60 psi) at 40xc2x0 C. for twelve hours. Purge the reaction with nitrogen and filter with celite. Concentrate the filtrate in vacuo and flash chromatograph with 15% ethyl acetate/hexane to yield the title compound (0.89 g, 72%) as a clear oil. MS calcd 380.2; MS (M+1) 381.2. 
To a suspension of 5% palladium on carbon (0.15 g) in methanol (50 mL)/triethylamine (1.0 mL) add a solution of Preparation 14 (0.58 g, 1.80 mmol)in methanol (10 mL). Place the mixture on a Parr shaker under hydrogen (60 psi) at 40xc2x0 C. for twelve hours. Purge the reaction with nitrogen and filter with celite. Concentrate the filtrate in vacuo and flash chromatograph with 15% ethyl acetate/hexane to yield the title compound (0.25 g, 43%) as a clear oil. MS calcd 294.1; MS (M+1) 295.1. 
This preparation follows that in Tet Letters 36, 31, 1995, 5461-5464. Cool a suspension of Preparation 17 (0.50 g, 1.54 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.23 g, 2.31 mmol) in anhydrous THF (25 mL) to xe2x88x9210xc2x0 C. in an ice/acetone bath, add isopropyl magnesium chloride (2.0M, 2.3 mL, 4.62 mmol), and stir the reaction for 30 minutes. Quench the reaction with saturated ammonium chloride. Add ethyl acetate and wash the organic layer washed with brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 50% ethyl acetate/hexane to yield the title compound (0.49 g, 90%) as a clear oil which is used without further characterization. 
Cool a suspension of Preparation 18 (0.48 g, 1.42 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.21 g, 2.13 mmol) in anhydrous THF (20 mL) to xe2x88x9210xc2x0 C. in an ice/acetone bath, add isopropyl magnesium chloride (2.0M, 2.1 mL, 4.20 mmol), and stir the reaction for 30 minutes. Quench the reaction with saturated ammonium chloride. Add ethyl acetate and wash the organic layer washed with brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 50% ethyl acetate/hexane to yield the title compound (0.46 g, 88%) as a clear oil which is used without further characterization. 
Cool a suspension of Preparation 19 (0.63 g, 2.53 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.26 g, 2.68 mmol) in anhydrous THF (30 mL) to xe2x88x9210xc2x0 C. in an ice/acetone bath, add isopropyl magnesium chloride (2.0M, 2.7 mL, 5.40 mmol), and stir the reaction for 30 minutes. Quench the reaction with saturated ammonium chloride. Add ethyl acetate and wash the organic layer washed with brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 50% ethyl acetate/hexane to yield the title compound (0.54 g, 76%) as a clear oil which is used without further characterization. 
Cool a suspension of Preparation 20 (0.50 g, 1.41 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.24 g, 2.12 mmol) in anhydrous THF (30 mL) to xe2x88x9210xc2x0 C. in an ice/acetone bath, add isopropyl magnesium chloride (2.0M, 2.1 mL, 4.20 mmol), and stir the reaction for 30 minutes. Quench the reaction with saturated ammonium chloride. Add ethyl acetate and wash the organic layer washed with brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 50% ethyl acetate/hexane to yield the title compound (0.31 g, 57%) as a clear oil which is used without further characterization. 
Cool a suspension of Preparation 21 (0.16 g, 0.45 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.07 g, 0.68 mmol) in anhydrous THF (10 mL) to xe2x88x9210xc2x0 C. in an ice/acetone bath, add isopropyl magnesium chloride (2.0M, 0.7 mL, 1.40 mmol), and stir the reaction for 30 minutes. Quench the reaction with saturated ammonium chloride. Add ethyl acetate and wash the organic layer washed with brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 50% ethyl acetate/hexane to yield the title compound (0.15 g, 87%) as a clear oil which is used without further characterization. 
Cool a suspension of Preparation 22 (0.25 g, 0.77 mmol)and N,O-dimethylhydroxylamine hydrochloride (0.11 g, 1.16 mmol) in anhydrous THF (20 mL) to xe2x88x9210xc2x0 C. in an ice/acetone bath, add isopropyl magnesium chloride (2.0M, 1.2 mL, 2.40 mmol), and stir the reaction for 30 minutes. Quench the reaction with saturated ammonium chloride. Add ethyl acetate and wash the organic layer washed with brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 50% ethyl acetate/hexane to yield the title compound (0.20 g, 74%) as a clear oil which is used without further characterization. 
Cool a suspension of Preparation 23 (0.91 g, 3.07 mmol)and N,O-dimethylhydroxylamine hydrochloride (0.45 g, 4.64 mmol) in anhydrous THF (20 mL) to xe2x88x9210xc2x0 C. in an ice/acetone bath, add isopropyl magnesium chloride (2.0M, 3.1 mL, 6.20 mmol), and stir the reaction for 30 minutes. Quench the reaction with saturated ammonium chloride. Add ethyl acetate and wash the organic layer washed with brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 50% ethyl acetate/hexane to yield the title compound (0.36 g, 36%) as a clear oil which is used without further characterization. 
Add phenyl lithium (1.0 M in cyclohexane, 1.3 mL, 1.34 mmol) into a solution of Preparation 24 (0.43 g, 1.22 mmol) in anhydrous THF 30 mL) at 0xc2x0 C. and stir the resulting solution for 30 minutes at 0xc2x0 C. Quench the reaction with saturated sodium bicarbonate. Add ethyl acetate and wash with brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 60% ethyl acetate/hexane to yield the title compound (0.28 g, 85%) as a clear oil. 1H NMR (CDCl3): 7.61 (d, J=7.4, 2H), 7.37-7.33 (m, 1H), 7.24-7.19 (m, 2H), 6.77 (d, J=2.7, 1H), 6.66 (d, J=9.0, 1H), 6.60 (dd, J=3.1, 9., 1H), 5.00 (dd, J=6.6, 17.8, 2H), 4.84 (s, 2H), 4.32-4.29 (m, 1H), 3.84-379 (m, 1H), 3.42 (s, 3H), 3.38 (s, 3H), 2.32-1.95 (m, 5H), 1.80-1.72 (m, 1H). 
To 0.31 mL (2.8 mmol) of p-bromofluorobenzene in 10 mL of THF at xe2x88x9278xc2x0 C. was added 3.4 mL (5.6 mmol) of 1.7 M tert-butyllithium. The mixture was cannulated into 0.7 g (2.0 mmol) of Preparation 24 in 10 mL of anhydrous THF at xe2x88x9278xc2x0 C. with magnetic stirring, and all was allowed to come to room temperature. After 5 hours, the mixture was partitioned between diethylether and saturated sodium bicarbonate aqueous. The organic layer was washed with water, saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and flash chromatographed on silica gel with 10% ethylacetate/hexanes to give the title compound (0.41 g, 53%). 1H NMR (CDCl3): 7.62 (m, 2H), 6.86 (m, 2H), 6.66 (m, 2H), 6.58 (m, 1H), 4.98 (dd, J=8.0, 17.0, 2H), 4.91 (s, 2H), 4.25 (m, 1H), 3.80 (m, 1H), 3.41 (s, 3H), 3.40 (s, 3H), 2.28-1.90 (m, 5H), 1.75 (m, 1H). 
To 0.33 mL (2.4 mmol) of 4-bromo-ethylbenezene in 10 mL of THF at xe2x88x9278xc2x0 C. was added 3.0 mL (5.0 mmol) of 1.7 M tert-butyllithium. The mixture was cannulated into 0.7 g (2.0 mmol) of Preparation 24 in 10 mL of anhydrous THF at xe2x88x9278xc2x0 C. with magnetic stirring, and all was allowed to come to room temperature. After 5 hours, the mixture was partitioned between diethylether and saturated sodium bicarbonate aqueous. The organic layer was washed with water, saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and flash chromatographed on silica gel with 10% ethylacetate/hexanes/0.4% triethylamine to give the title compound (0.46 g, 58%). 1H NMR (CDCl3): 7.54 (d, J=8.4, 2H), 7.03 (d, J=8.4, 2H), 6.76 (d, J=2.4, 1H), 6.67 (d, J=8.0, 1H), 6.58 (dd, J=8.0, 2.4, 1H), 5.00 (d, J=7.5, 1H), 4.96 (d, J=7.5, 1H), 4.85 (s, 2H), 4.26 (m, 1H), 3.80 (m, 1H), 3.40 (s, 3H), 3.38 (s, 3H), 2.58 (q, J=7.2, 2H), 2.26-1.92 (m, 5H), 1.65 (m, 1H), 1.17 (t, J=7.2, 3H). 
To 0.26 mL (1.8 mmol) of 4-bromo-xcex1,xcex1,xcex1-trifluorotoluene in 10 mL of THF at xe2x88x9278xc2x0 C. was added 2.15 mL (3.66 mmol) of 1.7 M tert-butyllithium. The mixture was cannulated into 0.59 g (1.67 mmol) of Preparation 24 in 10 mL of anhydrous THF at xe2x88x9278xc2x0 C. with magnetic stirring, and all was allowed to come to room temperature. After 18 hours, the mixture was partitioned between diethylether and saturated sodium bicarbonate aqueous. The organic layer was washed with water, saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and flash chromatographed on silica gel with 10% ethylacetate/hexanes/0.4% triethylamine to give the title compound (0.24 g, 33%). 1H NMR (CDCl3): 7.65 (d, J=8.8, 2H), 7.45 (d, J=8.8, 2H), 6.70 (s, 1H), 6.60 (m, 2H), 5.00 (d, J=7.5, 1H), 4.96 (d, J=7.5, 1H), 4.87 (s, 2H), 4.28 (m, 1H), 3.82 (m, 1H), 3.41 (s, 3H), 3.38 (s, 3H), 2.28 (m, 1H), 2.16-1.92 (m, 4H), 1.75 (m, 1H). 
To 0.63 g (2.8 mmol) of 3-bromo-O-methoxymethylphenol 10 mL of THF at xe2x88x9278xc2x0 C. was added 3.6 mL (6.1 mmol) of 1.7 M tert-butyllithium. The mixture was cannulated into 0.98 g (2.77 mmol) of Preparation 24 in 10 mL of anhydrous THF at xe2x88x9278xc2x0 C. with magnetic stirring, and all was allowed to come to room temperature. After 18 hours, the mixture was partitioned between diethylether and saturated sodium bicarbonate aqueous. The organic layer was washed with water, saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and flash chromatographed on silica gel with 10% ethylacetate/hexanes/0.1% tricthylamine to give the title compound (0.68 g, 57%). 1H NMR (CDCl3): 7.27 (d, J=7.8, 1H), 7.20 (d, J=1.6, 1H), 7.13 (m, 1H), 7.02 (dd, J=7.8, 1.6, 1H), 6.75 (d, J=3.2, 1H), 6.68 (d, J=7.8, 1H), 6.60 (dd, J=7.8, 3.2, 1H), 5.09 (s, 2H), 5.01 (d, J=6.4, 1H), 4.97 (d, J=6.6, 1H), 4.87 (s, 2H), 4.25 (m, 1H), 3.78 (m, 1H), 3.47 (m, 1H), 3.43 (s, 3H), 3.41 (s, 3H), 3.38 (s, 3H), 2.25-1.92 (m, 4H), 1.72 (m, 1H). 
To 0.31 mL (3.0 mmol) of 4-bromotoluene in 10 mL of THF at xe2x88x9278xc2x0 C. was added 3.6 mL (6.1 mmol) of 1.7 M tert-butyllithium. The mixture was cannulated into 0.98 g (2.77 mmol) of Preparation 24 in 10 mL of anhydrous THF at xe2x88x9278xc2x0 C. with magnetic stirring, and all was allowed to come to room temperature. After 5 hours, the mixture was partitioned between diethylether and saturated sodium bicarbonate aqueous. The organic layer was washed with water, saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and flash chromatographed on silica gel with 10% ethylacetate/hexanes to give the title compound (0.38 g, 36%). 1H NMR (CDCl3): 7.52 (d, J=7.6, 2H), 7.01 (d, J=8.0, 2H), 6.76 (d, J=3.0, 1H), 6.69 (d, J=8.8, 1H), 6.60 (dd, J=8.8, 3.0, 1H), 5.01 (d, J=6.8, 1H), 4.96 (d, J=6.6, 1H), 4.86 (s, 2H), 4.24 (m, 1H), 3.79 (m, 1H), 3.47 (m, 1H), 3.40 (s, 3H), 3.38 (s, 3H), 2.29 (s, 3H), 2.28-1.92 (m, 4H), 1.74(m, 1H).